A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adoptsa polyproline type II helix and inhibits encephalitogenic T cells in vitro

Complete activation of T cells requires two signals: an Ag-specific signal delivered via the TCR by the peptide-MHC complex and a second costimulatory signal largely provided by B7:CD28/CTLA-4 interactions. Previous studies h ave shown that B7 blockade can either ameliorate experimental autoimmune en cephalomyelitis by interfering with CD28 signaling or exacerbate the diseas e by concomitant blockade of CTLA-4 interaction. Therefore, we developed a functional CD28 mimic to selectively block B7:CD28 interactions. The design , synthesis, and structural and functional properties of the CD28 free pept ide, the end group-blocked CD28 peptide, and its retro-inverso isomer are s hown. The synthetic T cell-costimulatory receptor peptides fold into a poly proline type II helical structure commonly seen in regions of globular prot eins involved in transient protein-protein interactions. The binding determ inants of CD28 can be transferred onto a short peptide mimic of its ligand- binding region. The CD28 peptide mimics effectively block the expansion of encephalitogenic T cells in vitro suggesting the potential usefulness of th e peptides for the treatment of autoimmune disease conditions requiring dow n-regulation of T cell responses. The Journal of Immunology, 2001.